Prognostic Value of B-Type Natriuretic Peptide Level in Patients With Heart Failure With a Higher Left Ventricular Ejection Fraction

Abstract

Background: In heart failure (HF) patients with a higher left ventricular ejection fraction (LVEF), the B-type natriuretic peptide (BNP) level is yet to be fully assessed. Accordingly, we hypothesized that the BNP level should be higher in patients with a higher LVEF range based on the previous finding that such patients were associated with a worse prognosis.

Methods and Results: In our multicenter, prospective, observational cohort for the composite endpoint of all-cause death and readmission due to HF, including patients with LVEF >40% at hospital discharge, we obtained LVEF, E/e′, and BNP levels in 231 patients. The concurrent atrial fibrillation (AF) was confirmed by electrocardiogram. Patients were divided into HF with mildly reduced EF (HFmrEF), HF with preserved EF (HFpEF) with LVEF ≥50 and <60%, and HFpEF with LVEF ≥60%. The BNP levels were not significantly different among these groups (median [interquartile range]: 195 [110–348] vs. 242 [150–447] vs. 220 [125–320] pg/mL, respectively; P=0.422). In contrast, a BNP level of ≥377 pg/mL could significantly differentiate event-free survival (P<0.001). In the multi-covariate Cox proportional hazards model, the BNP level was significantly related to event-free survival independent of LVEF, E/e′, and concurrent AF.

Conclusions: Without confounding the effects of LVEF, E/e′, and concurrent AF, higher BNP levels are significantly and independently associated with event-free survival in HF patients with LVEF>40%.

In current heart failure (HF) clinical practice guidelines, HF is classified by the ranges of the left ventricular ejection fraction (LVEF), which are HF with reduced LVEF (HFrEF; LVEF ≤40%), HF with mildly reduced LVEF (HFmrEF; LVEF >40% and <50%), and HF with preserved LVEF (HFpEF; LVEF ≥50%).¹ We have reported that HF patients with a higher LVEF range had an unfavorable prognosis in our registry ‘Effects of β-blockers And renin-angiotensin SYstem inhibitors on the prognosis of patients with Heart Failure with preserved Ejection Fraction (EASY HFpEF)’.² LVEF, the ratio of early diastolic transmitral inflow velocity (E) to early diastolic mitral annular velocity (e′), that is E/e′, and the concurrent atrial fibrillation (AF) are independent parameters that were associated with an unfavorable prognosis.² In current clinical practice, assessing the B-type natriuretic peptide (BNP) level is crucial for diagnosing, managing, and predicting the prognosis in HF patients.^3,4 However, it has not been thoroughly assessed as to whether BNP levels for prognosis are independent of LVEF, E/e′, or the presence of concurrent AF in HF patients with LVEF >40%. Thus, we investigated the relationship between the BNP level and prognosis while considering the effect of other confounding parameters in the EASY HFpEF registry.

Methods

Study Design

The EASY HFpEF registry was a multicenter, prospective, observational cohort study primarily designed to evaluate whether using β-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was associated with improved event-free survival.² The study′s primary endpoint was a composite outcome of all-cause death and readmission due to HF.² The secondary endpoint was readmission due to HF.² We registered patients hospitalized with a diagnosis of acute decompensated HF according to the Framingham criteria and LVEF >40%, as determined by the modified Simpson’s method based on echocardiography at hospital discharge.² The study was performed in accordance with the Declaration of Helsinki, and the study protocol was approved by the institutional review board of Nagoya City University Graduate School of Medical Sciences and the review board of each site. The study was registered under Japanese UMIN Clinical Trials Registration (UMIN000017725). Written informed consent was obtained from each patient for participation in the study. The total number of study patients in the EASY HFpEF registry was 255.² However, BNP data were missed in 24 patients, and thus, in the present study, the analyses were conducted on a final total of 231 patients. The demographic, blood examination, echocardiography, and medication data of 231 patients are shown in Table 1. To investigate the relationship between the LVEF ranges and BNP levels, we divided the patients into 3 categories: HFmrEF; HFpEF with LVEF ≥50% and <60%; and HFpEF with LVEF ≥60%.

Table 1.

Comparisons of Clinical Characteristics, Blood Chemistry, and Medication Among the Patient Groups of HFmrEF, HFpEF With LVEF ≥50% and <60%, and HFpEF With LVEF ≥60%

	All patients (N=231)	(a) HFmrEF (n=69)	(b) HFpEF with LVEF ≥50% and <60% (n=79)	(c) HFpEF with LVEF ≥60% (n=83)	P value by ANOVA or K-W test	P value
						a vs. b*	a vs. c*	b vs. c*
Clinical background
Age (years)	74.8±10.7	71.4±11.6	75.3±9.98	77.2±9.99	0.004	0.081	0.003	0.758
Sex, female	110 (47.6)	22 (31.9)	34 (43.0)	54 (65.1)	<0.001	0.660	<0.001	0.024
Height (cm)	157±9.86	160±9.37	158±10.1	155±9.52	0.006	0.409	0.005	0.283
Body weight (kg)	57.2±13.9	57.9±12.8	57.7±13.7	56.0±15.0	0.640
Heart rate (beats/min)	69.8±15.4	73.5±18.3	70.1±14.8	66.5±12.5	0.018	0.531	0.014	0.404
Systolic BP (mmHg)	124±23.3	122±26.6	126±20.5	125±23.1	0.594
Clinical history
Hypertension	183 (79.2)	47 (68.1)	64 (81.0)	72 (86.7)	0.017	0.32	0.03	1.0
Diabetes	102 (44.2)	26 (37.7)	34 (43.0)	42 (50.6)	0.271
CAD	85 (36.8)	30 (43.5)	34 (43.0)	21 (25.3)	0.025	1.0	0.085	0.080
Prior MI	48 (20.8)	21 (30.4)	19 (24.1)	8 (9.6)	0.005	1.0	0.007	0.074
History of PCI	59 (25.5)	19 (27.5)	23 (29.1)	17 (20.5)	0.408
History of CABG	13 (5.6)	6 (8.7)	6 (7.6)	1 (1.2)	0.088
Valvular heart disease, ≤moderate	164 (71.0)	51 (74.0)	59 (74.7)	54 (65.1)	0.328
AF	117 (50.6)	27 (39.1)	42 (53.2)	48 (57.8)	0.062
Medication
β-blockers	163 (70.6)	58 (84.1)	50 (63.3)	55 (66.3)	0.012	0.024	0.062	1.0
ACEI/ARB	180 (77.9)	57 (82.6)	60 (75.9)	63 (75.9)	0.534
MRA	111 (48.1)	38 (55.1)	39 (49.4)	34 (41.0)	0.214
CCB	118 (51.1)	26 (37.7)	46 (58.2)	46 (55.4)	0.027	0.059	0.131	1.0
Statins	107 (46.3)	33 (47.8)	37 (46.8)	37 (44.6)	0.917
Diuretics	170 (73.6)	50 (72.5)	57 (72.2)	63 (75.9)	0.836
Digitalis	9 (3.9)	5 (7.2)	2 (2.5)	2 (2.4)	0.229
Echocardiography data
LVDd (mm; n=229)	48.2±6.78	52.7±6.64	47.7±6.20	45.0±5.29	<0.001	<0.001	<0.001	<0.001
LVDs (mm; n=229)	33.5±7.41	40.0±6.34	34.0±5.52	27.5±4.40	<0.001	<0.001	<0.001	<0.001
LVVed (mL; n=231)	91.5±32.7	111±34.4	90.2±30.6	76.3±23.7	<0.001	<0.001	<0.001	0.009
LVVes (mL; n=231)	41.6±20.8	61.6±19.6	41.3±14.5	25.2±9.22	<0.001	<0.001	<0.001	<0.001
LVEF (%; n=231)	56.0±9.81	44.9±2.75	54.3±2.87	67.0±5.07	<0.001	<0.001	<0.001	<0.001
LV IVSTd (mm; n=229)	10.8±2.57	10.5±2.21	10.8±2.39	11.2±2.96	0.271
LV PWTd (mm; n=229)	10.5±2.08	10.4±2.23	10.6±2.11	10.5±1.94	0.749
LVM (g; n=207)	186±71.3	206±72.2	185±72.6	172±66.8	0.021	0.288	0.017	0.818
LVMI (g/m3; n=207)	118±38.4	129±39.5	117±38.2	111±36.4	0.023	0.265	0.019	0.923
RWT (n=229)	0.44±0.11	0.40±0.10	0.45±0.09	0.48±0.11	<0.001	0.012	<0.001	0.397
E (cm/s; n=230)	81.2±27.3	71.4±25.5	81.0±24.5	89.6±28.4	<0.001	0.084	<0.001	0.119
e′ (cm/s; n=229)	6.20±2.29	5.81±2.23	6.02±2.11	6.68±2.42	0.045	1.0	0.056	0.200
E/e′ (n=229)	14.3±5.97	13.5±5.77	14.5±5.710	14.9±6.37	0.371
LAVI (mL/m3; n=215)	54.9±24.1	49.6±18.3	52.7±20.9	61.7±29.8	0.008	1.0	0.009	0.063
TRPG (mmHg; n=186)	25.7±9.60	21.3±6.66	25.9±9.56	28.9±10.3	<0.001	0.021	<0.001	0.181
Laboratory data
Hemoglobin (g/dL)	12.1±2.11	12.7±1.96	12.1±2.16	11.6±2.06	0.004	0.274	0.003	0.275
Serum albumin (g/dL)	3.57±0.49	3.61±0.49	3.52±0.51	3.58±0.46	0.568
Serum creatinine (mg/dL)	1.13±0.51	1.03±0.37	1.15±0.51	1.18±0.59	0.177
eGFR (mL/min/1.73 m2)	48.6 [37.8–61.0]	55.7 [45.1–66.2]	48.6 [37.8–59.0]	45.4 [34.5–59.0]	0.006	0.018	0.002	1.0

Data are presented as mean±SD, median [interquartile range], or n (%). *P values are those after adjustment by the Bonferroni or Steel-Dwass method; P<0.05 is considered significant. ACEI, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ANOVA, analysis of variance; ARB, angiotensin receptor blocker; BP, blood pressure; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CCB, calcium channel blocker; E, early diastolic transmitral inflow velocity; e′, early diastolic mitral annular velocity; eGFR, estimated glomerular filtration rate; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; IVSTd, interventricular septal wall thickness at end-diastole; K-W, Kruskal-Wallis; LAVI, left atrial volume index; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension; LVEF, left ventricular ejection fraction; LVM, left ventricular mass; LVMI, left ventricular mass index; LVVed, left ventricular end-diastolic volume; LVVes, left ventricular end-systolic volume; MI, myocardial infarction; MRA, mineralocorticoid receptor blocker; PCI, percutaneous coronary intervention PWTd; posterior wall thickness at end-diastole; RWT, relative wall thickness; TRPG, tricuspid regurgitation pressure gradient.

Echocardiography and BNP Measurement

Transthoracic echocardiography was performed at hospital discharge. All echocardiography examinations were performed according to the guidelines proposed by the American Society of Echocardiography and the European Association of Cardiovascular Imaging at each participating institute.^5,6 The e′ value was obtained as the averaged values from the septal and lateral sides. In our previous study, E/e′ ≥17.3 had a worse event-free survival regarding the primary endpoint.⁷ Echocardiography data are summarized in Table 1. The BNP levels were measured in each institute using commercially available and accuracy-controlled measurement kits. The BNP levels close to discharge were reported from each institution if they were measured more than once.

Statistical Analysis

Continuous variables are presented as mean±SD when normally distributed, and median and interquartile range (IQR) when non-normally distributed. Frequency data are presented as percentages. The significance of differences in parameters among the 3 groups was determined using analysis of variance (ANOVA) when data were normally distributed or the Kruskal-Wallis test when non-normally distributed. Post hoc comparisons between the groups were performed appropriately using the Bonferroni or Steel-Dwass correction. The relationship between the 2 parameters was determined using linear regression analysis. Differences in event-free survival were investigated using Kaplan-Meyer analysis with a log-rank test. The threshold value of the BNP level that identified the primary endpoint was assessed using receiver operating characteristic (ROC) curve analysis. The association of BNP levels on the outcome was evaluated using Cox proportional-hazards models. In the analysis, the other independent covariates were LVEF, E/e′, and the concurrence of AF, which were significantly associated with the primary endpoint of our original study.^2,7 In linear regression analysis and Cox proportional-hazards models, natural logarithm converted BNP level (lnBNP) was used for analysis. P<0.05 was considered significant. A biostatistics expert performed all analyses using R statistical software (R Foundation for Statistical Computing).

Results

A total of 62 patients reached the primary endpoint. Cardiovascular (CV) death was observed in 3 patients; 9 patients were readmitted due to CV diseases other than HF, and HF readmission was observed in 44 patients. Fifteen patients died due to non-CV reasons. The BNP levels were not significantly different among HFmrEF, HFpEF with LVEF ≥50% and <60%, and HFpEF with LVEF ≥60% (median [IQR]: 195 [110–348] vs. 242 [150–447] vs. 220 [125–320] pg/mL, respectively; P=0.422). In all patients, the threshold value of the BNP level that identified the primary endpoint in the ROC curve analysis was 377 pg/mL with an area under the curve of 0.635 (95% confidence interval 0.557–0.714; Figure 1A). Kaplan-Meier curve analysis showed that patients with BNP levels ≥377 pg/mL had worse event-free survival than those with BNP levels <377 pg/mL (P<0.001; Figure 1B). The lnBNP level was not correlated with LVEF (P=0.804); in contrast, it was significant but weakly correlated with E/e′ (r=0.166; P=0.012). The BNP level was significantly higher in patients with E/e′ ≥17.3 than in those with E/e′ <17.3 (median [IQR]: 296 [159–446] vs. 215 [109–310] pg/mL, respectively; P=0.013). The BNP level was also significantly higher in patients with AF than in those without (median [IQR]: 248 [159–451] vs. 190 [73.9–303] pg/mL, respectively; P=0.002). In the multi-covariate Cox proportional-hazards model for the primary endpoint, BNP level, LVEF (continuous value), E/e′, and the concurrence of AF were independently associated with event-free survival. In the multi-covariate Cox proportional-hazards model for the secondary endpoint, the same parameters were also independently associated with event-free survival (Table 2). As shown in Figure 2, Kaplan-Meier curves showed a worse prognosis regarding the primary endpoint in patients with BNP levels ≥377 pg/mL than in those with BNP levels <377 pg/mL across the LVEF ranges (P<0.001). As shown in Figure 3A, when the Kaplan-Meier curves were stratified by the concurrence of AF, compared with patients with BNP levels <377 pg/mL, those with BNP levels ≥377 pg/mL showed a worse prognosis regarding the primary endpoint (P<0.001). As shown in Figure 3B, when the Kaplan-Meier curves were similarly stratified by the E/e′ value of 17.3, compared with patients with a BNP level <377 pg/mL, those with a BNP level ≥377 pg/mL also showed a worse prognosis regarding the primary endpoint (P<0.001).

Figure 1.

Receiver operating characteristic curve analysis for the primary endpoint (A). The point indicated by the arrow corresponds to a 377 pg/mL B-type natriuretic peptide (BNP) level. The sensitivity and specificity of this method in detecting patients who reached the primary endpoint were 42% and 83%, respectively. The effect of the BNP levels on prognosis (B). Patients with BNP levels of ≥377 pg/mL had worse even-free survival compared with those with BNP levels <377 pg/mL.

Table 2.

Multi-Covariate Cox Proportional-Hazards Model for Event-Free Survival in (A) the Combined Endpoint of All-Cuse Death and Readmission Due to HF, and (B) the Readmission Due to HF

Independent covariates (n=229)	Partial regression coefficient	Hazard ratio (95% CI)	P value
(A)
LVEF, per 1% increase	0.036	1.036 (1.011–1.062)	0.005
Concurrent AF	1.048	2.851 (1.654–4.915)	<0.001
E/e′, per 1.0 increase	0.064	1.066 (1.026–1.107)	<0.001
lnBNP level per 1.0 pg/mL increase	0.322	1.380 (1.036–1.839)	0.028
(B)
LVEF, per 1% increase	0.039	1.039 (1.006–1.074)	0.021
Concurrent AF	1.442	4.230 (1.961–9.125)	<0.001
E/e′, per 1.0 increase	0.068	1.071 (1.023–1.121)	0.003
lnBNP level per 1.0 pg/mL increase	0.565	1.759 (1.191–2.597)	0.005

AF, atrial fibrillation; BNP, B-type natriuretic peptide; CI, confidence interval; E/e′, ratio of early diastolic transmitral inflow velocity (E) to early diastolic mitral annular velocity (e′); HF, heart failure; ln, natural logarithmic; LVEF, left ventricular ejection fraction.

Figure 2.

Effect of higher B-type natriuretic peptide (BNP) levels on prognosis in patient groups sorted by left ventricular ejection fraction (LVEF) range. The Kaplan-Meier curves show that BNP levels ≥377 pg/mL and higher LVEF ranges additively and significantly worsen prognosis.

Figure 3.

(A) Effect of higher B-type natriuretic peptide (BNP) levels on prognosis in patient groups with atrial fibrillation (AF) and without AF. The Kaplan-Meier curves show that BNP levels ≥377 pg/mL and the concurrence of AF additively and significantly worsen prognosis. (B) Effect of higher BNP levels on prognosis in patient groups with E/e′ ≥17.3 and those with E/e′ <17.3. The Kaplan-Meier curves show that BNP levels ≥377 pg/mL and E/e′ ≥17.3 additively and significantly worsen prognosis.

Discussion

The main findings of this study are as follows: (1) the BNP levels were not significantly different across the LVEF ranges in HF patients with LVEF >40%; (2) a BNP level of ≥377 pg/mL could differentiate event-free survival in those patients; and (3) the BNP level was significantly associated with event-free survival independent of LVEF, E/e′, and concurrent AF.

Relationship Between BNP Levels and LVEF Ranges

We hypothesized that the BNP level should be higher in patients with a higher LVEF range based on the findings that a higher LVEF range was associated with a worse prognosis.^2,8,9 However, in the present study, we demonstrated no difference in the BNP levels across the LVEF ranges in HF patients with LVEF >40%. The inconsistency between the hypothesis and the study results needs to be discussed. In linear regression analysis, we found no significant relationship between the lnBNP level and LVEF. We also observed no confounding for prognosis among the lnBNP level, LVEF, E/e′, and concurrence of AF in the Cox proportional hazards model. These statistical results dismissed our hypothesis. In contrast, the patients with BNP levels ≥377 pg/mL had worse event-free survival than those with BNP levels <377 pg/mL in this study. The summarized findings are consistent with the consensus statement from the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America, and the Japanese Heart Failure Society, indicating that a higher BNP level is related to poor prognosis in HF patients regardless of the LVEF range.⁴ Higher values in both parameters are independently related to a worse prognosis.

Pathophysiology of BNP Elevation in a Higher LVEF Range

In patients with HF and a higher LVEF range, LV hypertrophy and LV concentric remodeling are frequent coexisting findings.^10,11 A similar fashion was observed in our cohort.^2,7 It has been acknowledged that patients with LV hypertrophy or concentric remodeling generally have elevated BNP levels.^12–14 In contrast, Iwanaga et al. previously reported that the BNP level strongly reflects LV end-diastolic wall stress (WS) more than LV end-diastolic pressure, LVEF, or LV end-systolic WS not only in patients with HFrEF but also in patients with HFpEF.¹⁵ The following formula calculates LV end-diastolic meridional WS:¹⁶

LV end-diastolic WS (kdyne/cm²) = 0.334*LVEDP*(LVID) / WT(1 + WT/LVID),

where LVEDP is LV end-diastolic pressure (mmHg), LVID is LV internal diameter at end-diastole (cm), and WT is an LV end-diastolic wall thickness (cm).

As theoretically expected, LVEF and LVID are inversely correlated.¹⁷ Thus, based on this formula, in HFpEF patients with a higher LVEF range, LV end-diastolic WS should decrease in higher LVEF ranges if LVEDP is not different across the ranges. In our patients, E/e′, a surrogate of LVEDP, did not differ among the 3 groups classified by LVEF range.⁷ In this context, diminishing LV end-diastolic diameter due to LV concentric remodeling with or without LV hypertrophy should decrease the BNP level in patients with HFpEF. Therefore, in HFpEF patients with a higher LVEF range, increased BNP secretion should depend on mechanisms other than the stretch of the myocardium, such as hypertrophied myocardium, chronic systemic inflammation, and oxidative stress.^14,18–20 Paulus et al. proposed a theoretical framework for developing HFpEF: they proposed that comorbidities-induced systemic inflammation leads to coronary microvascular endothelial inflammation and subsequent LV concentric remodeling/hypertrophy and stiffness.²⁰ Less increased BNP levels in HFpEF than HFrEF may attenuate the beneficial effect of BNP on cardiac remodeling in HFpEF.^20,21 van Veldhuisen et al. reported that BNP levels are lower in patients with HFpEF than in patients with HFrEF, but for a given BNP level, the prognosis in patients with HFpEF is as poor as in those with HFrEF.²²

Effect of BNP Level Increase on Prognosis in Patients With a High E/e′ or With AF

The finding that the BNP level was significantly elevated in patients with LV diastolic dysfunction and those with AF has been well acknowledged.^23,24 We consider that the BNP secretion in our patients was related to LV diastolic dysfunction and the existence of AF to some extent. However, as a prognosis parameter, the BNP level was statistically independent of E/e′ and the concurrence of AF in the multi-covariate Cox proportional hazards model. Thus, in addition to the unfavorable effects of higher E/e′ and the concurrence of AF on prognosis,^2,7 an increase in BNP level is additively related to a worse prognosis.

Study Limitations

Although the number of study participants was relatively small in our cohort, which included HF patients who experienced decompensation of HF, the event rate was dose to 30%.² This allowed us to observe significant findings in several key parameters, such as LVEF, E/e′, the concurrence of AF, and the BNP level for prognosis. The study design, a multi-center prospective observational cohort study, strengthened the reliability of results despite the limited number of participants.

Conclusions

BNP levels ≥377 pg/mL are significantly associated with an unfavorable prognosis independent of LVEF, E/e′, and concurrence of AF in HF patients with LVEF >40%. Thus, measuring the BNP level in HF patients with LVEF >40% provides additive clinical information on predicting prognosis while considering the significant effects of LVEF, E/e′, and concurrent AF. The BNP levels in HF patients with LVEF >40% may reflect cardiac conditions that were not detectable using conventional echocardiography parameters.

Sources of Funding

This work was supported by the Scientific Research Funding (no. 23K07484) from the Japan Society for the Promotion of Science.

Disclosures

Y.S. is an Associate Editor of Circulation Reports. Y.K. received scholarships from Abbott Japan, Otsuka Pharma, Biotronik Japan, Japan Lifeline, Medtronic Japan, and Boston Scientific. K.D. received lecture fees from Novartis Pharma., Otsuka Pharma, Daiichi Sankyo, and Nippon Boehringer Ingelheim, and research grants from Otsuka Pharma, and Daiichi Sankyo. T.O. received lecture fees from Ono Yakuhin, Novartis Pharma, and Otsuka Pharma, and research grants from Ono Yakuhin, and Amgen Astellas. K.K. received lecture fees from Daiichi Sankyo. N.O., S. Kikuchi, N.I., H.T., K.I., K.H., E.S., and S. Kitada have nothing to declare.

IRB Information

The study protocol was approved by the institutional review board of Nagoya City University Graduate School of Medical Sciences (No. 1019).

Data Availability

The full data set is available on request with permission from the institutional review board of Nagoya City University Graduate School of Medical Sciences.

Appendix

EASY HFpEF Investigators: Nobuyuki Ohte, Shohei Kikuchi, Noriaki Iwahashi, Yoshiharu Kinugasa, Kaoru Dohi, Hiroyuki Takase, Katsuji Inoue, Takahiro Okumura, Kenta Hachiya, Emiyo Sugiura, Kenya Kusunose, Shuichi Kitada, Yoshihiro Seo, Kumiko Masai, Toyoaki Murohara, Hiroyuki Iwano, Mitsushige Murata, Hirotsugu Yamada, Mai Iwataki, Satoshi Yuda, and Takeshi Suzuki.

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